Pro-Oncogenic Role of a Mitochondrial Lipid Kinase in CLL

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PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is an adult B-cell malignancy accounting for about a third of leukemia diagnoses in the US. While B-cell receptor (BCR)-signal-inhibitors are changing the management of CLL, these are not curative and resistance can develop; often leading to more aggressive disease. Given this, understanding the molecular events driving CLL oncogenesis and therapeutic resistance warrants in-depth investigation. CLL is a disease characterized by extensive clonal proliferation and accumulation of malignant B lymphocytes in the blood, bone marrow, spleen, and lymph nodes. CLL shows remarkable clinical heterogeneity, with some patients pursuing an indolent course, while others progress rapidly and require early treatment. In the past 10 years, new insights into the biological function of a mitochondrial lipid kinase, acylglycerol kinase (AGK), as a key oncogene that is highly expressed in a range of tumor types, including prostate cancer, breast cancer, cervical squamous cell carcinoma, and esophageal squamous cell carcinoma have been established. Most recently, we found aberrantly high level expression of AGK in CLL cells from ~60% of pre-therapy CLL patients. However, the mechanism of aberrant upregulation of AGK in CLL cells, and its precise functional contributions to CLL cell biology and pathogenesis remain unknown. Interestingly, we detected nuclear/cytoplasmic localization of AGK in some CLL clones suggesting its multi-functional role. In line with this, we found that siRNA- mediated depletion of AGK in primary CLL cells resulted in marked inhibition of constitutively active multiple signal mediators including AKT, Erk1/2, LYN, BTK (downstream targets of BCR signal) and JAK2. Our preliminary findings also indicate that MYC may regulate AGK expression in CLL cells. Our combined data suggest that aberrant expression of AGK may potentiate cell survival signals including BCR and JAK2 in some CLL clones resulting in resistance to BCR-targeted therapies. Therefore, the central hypothesis of this application is that aberrant expression of AGK in some CLL clones represents highly aggressive CLL with shorter time to therapy. We also postulate that AGK upregulation potentiates CLL cell survival signals and resistance to BCR- targeted agents. We propose – Aim 1: Evaluate if aberrant expression of AGK in CLL cells drives disease progression; Aim 2: Define the mechanism of AGK upregulation and its role in CLL cell biology, signaling and potential as a therapeutic target. The proposed in-depth studies will assess if “high AGK” level in CLL cells serves as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of AGK aberrant expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies have enormous potential to establish a new prognostic parameter and therapeutic avenue via targeting AGK in CLL cells with or without the current BCR-targeted therapy, ibrutinib.